Sarah Boudová

Submicroscopic malaria infection during pregnancy and the impact of intermittent preventive treatment

BackgroundMalaria during pregnancy results in adverse outcomes for mothers and infants. Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) is the primary intervention aimed at reducing malaria infection during pregnancy. Although submicroscopic infection is common during pregnancy and at delivery, its impact throughout pregnancy on the development of placental malaria and adverse pregnancy outcomes has not been clearly established.MethodsQuantitative PCR was used to detect submicroscopic infections in pregnant women enrolled in an observational study in Blantyre, Malawi to determine their effect on maternal, foetal and placental outcomes. The ability of SP to treat and prevent submicroscopic infections was also assessed.Results2,681 samples from 448 women were analysed and 95 submicroscopic infections were detected in 68 women, a rate of 0.6 episodes per person-year of follow-up. Submicroscopic infections were most often detected at enrolment. The majority of women with submicroscopic infections did not have a microscopically detectable infection detected during pregnancy. Submicroscopic infection was associated with placental malaria even after controlling for microscopically detectable infection and was associated with decreased maternal haemoglobin at the time of detection. However, submicroscopic infection was not associated with adverse maternal or foetal outcomes at delivery. One-third of women with evidence of placental malaria did not have documented peripheral infection during pregnancy. SP was moderately effective in treating submicroscopic infections, but did not prevent the development of new submicroscopic infections in the month after administration.ConclusionsSubmicroscopic malaria infection is common and occurs early in pregnancy. SP-IPT can clear some submicroscopic infections but does not prevent new infections after administration. To effectively control pregnancy-associated malaria, new interventions are required to target women prior to their first antenatal care visit and to effectively treat and prevent all malaria infections.

Impact of persistent HIV replication on CD4 negative Vγ2Vδ2 T cells.

BACKGROUND CD4- Vγ2Vδ2 T cells are depleted during human immunodeficiency virus (HIV) infection but can recover to near normal levels in patients who spontaneously control viremia in the absence of therapy. By contrasting Vγ2Vδ2 T-cell numbers, phenotype, and T-cell receptor (TCR) repertoire, we investigate the dynamic tension between active immunity and progressive T-cell destruction during persistent viremia. METHODS Peripheral blood Vγ2Vδ2 T-cell levels and phenotypes were characterized by flow cytometry. Lymphoproliferation assays measured functional responses. Spectratyping characterized damage to the TCR repertoire. RESULTS Levels, responses to antigen and the proportion of T effector memory Vγ2Vδ2 T cells in patients with persistent viremia, were intermediate between patients with natural virus suppression (NVS) and patients receiving antiretroviral therapy. Damage to the TCR γ-2 chain repertoire and depletion of CD56+ Vγ2Vδ2 T cells were more pronounced in viremic patients, compared with antiretroviral therapy recipients and patients with natural virus suppression. CONCLUSIONS Characteristics of Vγ2Vδ2 T cells in viremic patients reflect both active responses (increasing cell numbers, better antigen responses, and higher proportion of effector memory cells) and ongoing damage (repertoire changes and loss of CD56+ cells). Unlike patients who control viremia to undetectable levels, Vγ2Vδ2 T cells are diminished during persistent viremia and may eventually be lost because of progressive destruction of the TCR repertoire.

Pregnant women are a reservoir of malaria transmission in Blantyre, Malawi

BackgroundDuring pregnancy, women living in malaria-endemic regions are at increased risk of malaria infection and can harbour chronic placental infections. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPTp) is administered to reduce malaria morbidity. It was hypothesized that the presence of placental malaria infection and SP-IPTp use would increase the risk of peripheral blood gametocytes, the parasite stage that is transmissible to mosquitoes. This would suggest that pregnant women may be important reservoirs of malaria transmission.MethodsLight microscopy was used to assess peripheral gametocytaemia in pregnant women enrolled in a longitudinal, observational study in Blantyre, Malawi to determine the association between placental malaria and maternal gametocytaemia. The relationship between SP-IPTp and gametocytaemia was also examined.Results2,719 samples from 448 women were analysed and 32 episodes of microscopic gametocytaemia were detected in 27 women. At the time of enrolment 22 of 446 women (4.9%) had gametocytaemia and of the 341 women for whom there was sufficient sampling to analyse infection over the entire course of pregnancy, 27 (7.9%) were gametocytaemic at least once. Gametocytaemia at enrolment was associated with placental malaria, defined as malaria pigment or parasites detected by histology or qPCR, respectively (OR: 32.4, 95% CI: 4.2-250.2), but was not associated with adverse maternal or foetal outcomes. Administration of SP-IPTp did not affect gametocyte clearance or release into peripheral blood.ConclusionsGametocytaemia is present in 5% of pregnant women at their first antenatal visit and associated with placental malaria. SP-IPTp does not alter the risk of gametocytaemia. These data suggest that pregnant women are a significant reservoir of gametocyte transmission and should not be overlooked in elimination efforts. Interventions targeting this population would benefit from reaching women prior to first antenatal visit.

Prolonged PD1 Expression on Neonatal Vδ2 Lymphocytes Dampens Proinflammatory Responses: Role of Epigenetic Regulation

A successful pregnancy depends on the maintenance of tolerance at the fetal–maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human Vδ2 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal Vδ2 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal–maternal interface. Neonatal Vδ2 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-α production and degranulation) by neonatal Vδ2 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal Vδ2 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control Vδ2 cell inflammatory responses during fetal life.

Placental but Not Peripheral Plasmodium falciparum Infection During Pregnancy Is Associated With Increased Risk of Malaria in Infancy

Pregnancy-associated Plasmodium falciparum infection impacts the health of mothers and newborns, but little is known about the effects of these infections on infant susceptibility to malaria. We followed 473 mother-infant pairs during pregnancy and through 2 years of age. We observed that children born to mothers with placental malaria, but not those born to mothers with peripheral infection without evidence of placental sequestration, had increased risk of malaria during the first year of life compared with children born to mothers with no malaria during pregnancy. Malaria infections with placental sequestration have long-lasting impact on infant susceptibility to malaria infection.

Mother-Newborn Pairs in Malawi Have Similar Antibody Repertoires to Diverse Malaria Antigens

ABSTRACT Maternal antibodies may play a role in protecting newborns against malaria disease. Plasmodium falciparum parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria-specific antibodies have been shown to cross the placenta, the extent to which antibodies that respond to the full repertoire of diverse antigens are transferred from the mother to the infant has not been explored. Understanding the breadth of maternal antibody responses and to what extent these antibodies are transferred to the child can inform vaccine design and evaluation. We probed plasma from cord blood and serum from mothers at delivery using a customized protein microarray that included variants of malaria vaccine target antigens to assess the intensity and breadth of seroreactivity to three malaria vaccine candidate antigens in mother-newborn pairs in Malawi. Among the 33 paired specimens that were assessed, mothers and newborns had similar intensity and repertoire of seroreactivity. Maternal antibody levels against vaccine candidate antigens were the strongest predictors of infant antibody levels. Placental malaria did not significantly impair transplacental antibody transfer. However, mothers with placental malaria had significantly higher antibody levels against these blood-stage antigens than mothers without placental malaria. The repertoire and levels of infant antibodies against a wide range of malaria vaccine candidate antigen variants closely mirror maternal levels in breadth and magnitude regardless of evidence of placental malaria. Vaccinating mothers with an effective malaria vaccine during pregnancy may induce high and potentially protective antibody repertoires in newborns.

Reply to Hartjen et al

To the Editor—Hartjen et al compared γδ T-cell levels and phenotypes in human immunodeficiency virus (HIV)–infected patients. Their letter describes differences from our published results [1] and questions whether the HIV-associated changes in Vδ2 T cells reported by us [2] are found in most of HIV-infected patients. The control group in the study by Hartjen et al, represented in Figure 1C of their report, has a mean value of approximately 1% Vδ2 T cells among total lymphocytes in blood. This value is on the low end of reported levels for Vδ2 cells among healthy donors in any of our previous studies [2] or in a study of sex and age effects on Vδ2 T cells [3]. If we use a median value from the Hartjen et al data, Vδ2 levels for their control group would be <1% lymphocytes; normally, we would expect this value to be closer to 2% for a healthy donor group with a median age of 37 years. Hartjen et al disagreed with our conclusion that the effector memory subset of Vδ2 T cells tends to be lower among HIV-positive groups. However, they studied terminally differentiated T cells [4] and did not focus on the effector memory subset, as defined previously [5]. Hartjen et al also raised a concern about our conclusion that CD56+ Vδ2 T cells are depleted in HIV disease except among natural viral suppressors [6] (designated “EC” for “elite controllers” in their letter). Specifically, they reported elevated CD56+ Vδ2 T cells in patients with high viremia with a mean level of 20% CD56+ Vδ2 T cells. We consider this value to be low compared with that for healthy, matched controls [6]. The control donors in Figure 1E in the report by Hartjen et al also have very low levels of CD56 expression on Vδ2 T cells, especially compared with our previous studies. Among HIV-negative control donors who we studied (matched for age and sex), only 3 of 28 whites and 10 of 29 African Americans had <20% CD56+ Vδ2 T cells in blood. This contrasts sharply with the mean value shown by Hartjen et al, which is approximately 7% CD56+ Vδ2 T cells among control donors. Our conclusions were based on extensive databases for healthy controls and HIV-positive donors from studies conducted in North America, Europe, Western Africa, and China [2]. On the basis of multiple phenotyping and T-cell receptor sequencing studies [2, 7], we are confident that HIV infection drives specific depletion of the Vδ2 subset and lowers circulating levels of CD56+ cytotoxic effectors. We are unable to account for differences between our studies and the report from Hartjen et al, especially concerning the low expression of CD56 and low abundance of Vδ2 T cells among their control donors.

Risk-Based Hepatitis C Screening in Pregnancy Is Less Reliable Than Universal Screening: A Retrospective Chart Review

Abstract Current guidelines recommend only hepatitis C virus (HCV) risk-based screening during pregnancy. We examined screening practices at a major medical center and found inconsistent risk-based screening and the presence of HCV among women with no known risk factors. We make a case for the implementation of universal HCV screening during pregnancy.

F6 γδ T Cells in HIV-Infected Individuals With Persistent Viremia

BackgroundPersistent viremia (PV) patients not receiving HAART had persistent vRNA <12,000 copies. We compared &ggr;&dgr; T cells in PV patients with similar values for natural virus suppressors (NVS), treated patients (ARV group) and controls. Our goal was to understand the impact of chronic viremia on V&ggr;2V&dgr;2 T cells. MethodsPeripheral blood &ggr;&dgr; T cell levels and phenotypes were characterized by flow cytometry. Lymphoproliferation measured functional responses. Spectratyping characterized damage to the T cell receptor (TCR) repertoire. ResultsLevels, responses to antigen and T effector memory subset of &ggr;&dgr; T cells in PV, were intermediate between NVS and ARV groups. Damage to the TCR &ggr;-2 chain repertoire and depletion of CD56+ &ggr;&dgr; T cells were more pronounced in PV compared to ARV or NVS patients. ConclusionsCell counts, antigen responses and effector memory V&ggr;2V&dgr;2 T cells were elevated in PV compared to treated patients, consistent with an ongoing &ggr;&dgr; T cell response. The altered TCR &ggr;-2 chain repertoire and fewer CD56+ cells evidenced HIV-specific damage to this subset. Characteristics of V&ggr;2V&dgr;2 T cells in PV patients reflect both active responses and ongoing damage. The balance between cell activation and depletion is consistent with low viremia and slow progression.